Neuropsychobiology 2010;62:36–42 Published online: May 7, 2010

DOI: 10.1159/000314308

Lithium’s Emerging Role in the Treatment

of Refractory Major Depressive Episodes:
Augmentation of Antidepressants
Michael Bauer a, b Mazda Adli b, c Tom Bschor a, b, d Maximilian Pilhatsch a
Andrea Pfennig a, b Johanna Sasse a, b Rita Schmid e Ute Lewitzka a, b
a
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische
Universität Dresden, Dresden, b The International Group for the Study of Lithium-Treated Patients, IGSLI,
c
Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Charité Campus Mitte, and
d
Department of Psychiatry, Schlosspark-Clinic, Berlin, and e Department of Psychiatry and Psychotherapy,
University Medical Center Regensburg, Regensburg, Germany

Key Words needed-to-treat of 5. The meta-analysis revealed a mean re-

Lithium ⴢ Augmentation treatment strategies ⴢ
Antidepressants ⴢ Treatment-resistant depression
Abstract
Background: The late onset of therapeutic response and a
relatively large proportion of nonresponders to antidepres-
sants remain major concerns in clinical practice. Therefore,
there is a critical need for effective medication strategies
that augment treatment with antidepressants. Methods: To
review the available evidence on the use of lithium as an
augmentation strategy to treat depressive episodes. Re-
sults: More than 30 open-label studies and 10 placebo-con-
trolled double-blind trials have demonstrated substantial
efficacy of lithium augmentation in the acute treatment of
depressive episodes. Most of these studies were performed
in unipolar depression and included all major classes of an-
tidepressants, however mostly tricyclics. A meta-analysis in-
cluding 10 randomized placebo-controlled trials has provid-
ed evidence that lithium augmentation has a statistically sig-
nificant effect on the response rate compared to placebo
with an odds ratio of 3.11, which corresponds to a number-
sponse rate of 41.2% in the lithium group and 14.4% in the
placebo group. One placebo-controlled trial in the continu-
ation treatment phase showed that responders to acute-
phase lithium augmentation should be maintained on the
lithium-antidepressant combination for at least 12 months
to prevent early relapses. Preliminary studies to assess ge-
netic influences on response probability to lithium augmen-
tation have suggested a predictive role of the –50T/C single
nucleotide polymorphism of the GSK3␤ gene. Conclusion:
Augmentation of antidepressants with lithium is currently
the best-evidenced augmentation therapy in the treatment
of depressed patients who do not respond to antidepres-
sants. Copyright © 2010 S. Karger AG, Basel
History of Lithium in Depression
Since the discovery of lithium in modern psychiatry
in 1949, lithium has been mainly considered as a prophy-
lactic treatment for bipolar disorders and an acute treat-
ment of mania. Less attention has been given to lithium

© 2010 S. Karger AG, Basel Michael Bauer, MD, PhD

0302–282X/10/0621–0036$26.00/0 Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus
Fax +41 61 306 12 34 Technische Universität Dresden, Fetscherstrasse 74, DE–01307 Dresden (Germany)
E-Mail karger@karger.ch Accessible online at: Tel. +49 351 458 2772, Fax +49 351 458 4324
www.karger.com www.karger.com/nps E-Mail michael.bauer @ uniklinikum-dresden.de
and its potential value to treat and prevent acute depres-
sive episodes in unipolar depression [1, 2]. As early as in
the 1960s and 70s, the antidepressant effect of lithium
was investigated by numerous studies. Although there is
quite some evidence from these studies for an antidepres-
sive efficacy, lithium has never been used broadly as an
antidepressant medication in unipolar and bipolar de-
pressed patients in clinical practice. The maintenance
properties of lithium were investigated since the late
1950s in both bipolar and unipolar affective illness. Many
of these studies which focused on bipolar disease also had
substantial data on the prophylactic effects of lithium in
preventing the recurrence of unipolar depression. A re-
cent comprehensive review of these studies shows that
lithium prevents the recurrence of unipolar depression
[1]. However, despite these findings the evidence failed to
convince practitioners to use lithium to treat acute and
prophylactic depressive disorders. This might be due to
its relatively narrow therapeutic range of application and
the necessity with lithium treatment to monitor lithium
serum level regularly. The focus of this article is on an-
other effective application of lithium in the treatment of
depressive disorders that emerged since the 1980s: lithi-
um augmentation of antidepressants.
Augmentation Therapy in Depression
Although there are many drugs available for the treat-
ment of major depression, the overall treatment outcome
of depressed patients is usually far from optimal. Regard-
less of the initial choice of antidepressant, about 30–50%
of patients with a major depressive episode will not re-
spond sufficiently to adequately performed first-line
treatment [3]. Numerous treatment strategies have been
described for use in antidepressant nonresponder and
treatment-resistant depression [4, 5]. Augmentation
treatment strategies involve adding a second drug other
than an antidepressant to the treatment regimen when no
response or only partial response has been achieved, with
the goal of enhancing treatment. Augmentation agents
include lithium, thyroid hormones, atypical neurolep-
tics, anticonvulsants, stimulants and buspirone. One ad-
vantage of augmentation is that it eliminates the period
of transition between 1 antidepressant to another and
builds on the partial response. Consequently, when they
work, augmentation strategies can have a rapid effect.
Secondly, augmentation is of benefit for patients who
have had some response and may be reluctant to risk los-
ing that improvement [3].
Lithium Augmentation
Of these strategies, lithium augmentation therapy is
among the best-studied ones [6]. Lithium salts have been
used to augment the efficacy of antidepressant medica-
tions for more than 25 years. The first study to test this
hypothesis in patients with major depression was per-
formed by de Montigny et al. [7]. They reported a dra-
matic response within 48 h to the addition of lithium in
8 patients who had not responded to at least 3 weeks of
treatment with tricyclic antidepressants. The efficacy of
the combination and rapidity of response has led many
clinical research groups to pursue study of this treatment
intervention. Subsequent randomized controlled trials
have confirmed de Montigny’s initial findings from 1981
with more than 30 open-label and comparator studies
including more than 500 depressed patients being pub-
lished [8]. In these studies, the duration of antidepres-
sant before treatment ranged between 3 and 7 weeks with
a mean of 4.5 weeks; the subsequent lithium augmenta-
tion therapy lasted between 2 days and 14 weeks with a
mean duration of about 30 days. The antidepressants
used in the trials included agents from different groups;
among them were selective serotonin reuptake inhibitors
(SSRIs), tri- and tetracyclic antidepressants, and mono-
amine oxidase inhibitors. The dosages of the antidepres-
sants used were not reported in all trials. The dosages of
lithium carbonate ranged between 300 and 1,500 mg/
day. The response rates ranged widely between 100 and
23.5% with a median of 56%; 10 of 17 open-label studies
found response rates to lithium augmentation of 50% or
more.
A recent meta-analysis addressing the question pooled
10 randomized, double-blind, placebo-controlled trials
and included 269 mostly unipolar depressed patients [9].
Lithium dosage, duration of treatment and other charac-
teristics of the studies are detailed in table 1. Lithium had
a significant positive effect versus placebo with an odds
ratio of 3.11, which corresponds to a number-needed-to-
treat of 5. Table 1 shows the odds ratio for subjects re-
sponding to the treatment in each study by year of publi-
cation.
However, 5 of the studies pooled did not show a sig-
nificant difference. Reasons for the negative findings may
be low power [10–12], use of insufficient lithium doses
[13], too short a duration of treatment [10, 12], and con-
cerns about the efficacy of lithium augmentation with
noradrenergic antidepressants [14, 15]. Previous studies
had demonstrated that only doses of lithium carbonate
higher than 600 mg/day and a duration of 7 days were
useful in augmenting therapies [16].
Neuropsychobiology 2010;62:36–42 37
Table 1. Results of randomized, placebo-controlled lithium augmentation studies in depression

Study Subjects Antidepressant Lithium dosage (serum level) and Fixed effects: Response criteria;
duration odds ratioa (95% CI) response rates

Heninger et al. 14 UP, 1 BP various TCAs lithium carbonate 900–1,200 mg/day 23.57 (1.00–556.08) decrease of 2 or more
[47], 1983 12 F, 3 M and tetracyclics (0.5–1.1 mEq/l) points on SCRS;
mean age 50 years 12 days lithium: 62.5%
placebo: 0%
Kantor et al. 7 UP various TCAs lithium carbonate 900 mg/day 3.00 (0.09–102.05) ≥40% decrease in
[10], 1986 sex nr 48 h HAM-D score;
mean age nr lithium: 25%
placebo: 0%
Zusky et al. 16 UP various TCAs lithium carbonate 300 mg/day first 1.80 (0.21–15.41) final HAM-D score ≤7;
[11], 1988 13 F, 3 M and MAOIs week, 900 mg/day second week lithium: 38%
mean age 45 years 14 days placebo: 25%
Schöpf et al. 18 UP, 9 BP various lithium carbonate 600–800 mg/day 27.00 (1.35–541.57) ≥50% decrease in HAM-D;
[30], 1989 19 F, 8 M antidepressants (0.6–0.8 mEq/l) lithium: 50%
mean age 54 years 7 days placebo: 0%
Browne et al. 14 UP, 3 BP various TCAs lithium carbonate 900 mg/day 3.00 (0.35–25.87) ≥50% decrease in HAM-D;
[12], 1990 10 F, 7 M and tetracyclics 48 h lithium: 43%
mean age 42 years placebo: 20%
Stein and 34 UP various TCAs lithium carbonate 250 mg/day or 0.50 (0.08–3.19) ≥50% decrease in HAM-D;
Bernadt 27 F, 7 M 750 mg/day lithium (250 mg): 18%
[13], 1993 mean age 47 years 21 days lithium (750 mg): 44%
placebo: 22%
Joffe et al. 33 UP various TCAs lithium carbonate 900 mg/day 4.88 (1.01–23.57) ≥50% decrease in HAM-D;
[21], 1993 18 F, 15 M (>0.55 mEq/l) lithium: 52%
mean age 37 years 14 days placebo: 18.7%
Katona et al. 61, polarity nr SSRI and TCA lithium 800 mg/day (0.6–1 mmol/l) 3.21 (1.09–9.48) ≥50% decrease in HAM-D;
[48], 1995 35 F, 26 M 42 days lithium: 53%
mean age 40 years placebo: 25%
Baumann et al. 23 UP, 1 BP SSRI lithium carbonate 800 mg/day 9.00 (1.27–63.89) ≥50% decrease in HAM-D;
[49], 1996 17 F, 7 M (citalopram) (0.5–0.8 mmol/l) lithium: 58%
mean age 41 years 7 days placebo: 14%
Nierenberg et al. 35 UP TCA lithium carbonate 900 mg/day 0.58 (0.08–4.01) ≥50% decrease in HAM-D;
[14], 2003 16 F, 19 M (nortriptyline) lithium: 12.5%
mean age 38 years placebo: 20%

UP = Unipolar; BP = bipolar; F = female; M = male; nr = not reported; MAOI = monoamine oxidase inhibitor; TCA = tricyclic antidepressant; HAM-
D = Hamilton Depression Rating Scale; SCRS = Short Clinical Rating Scale; CI = confidence interval.
a
All studies: odds ratio 3.11 (1.80–5.37); data from meta-analysis.

Since the first meta-analysis [16], only 1 placebo-con-
trolled study has been published [14]. As noted on the
original meta-analysis published in 1999 [16], a new neg-
ative study would have to include more than 2,500 pa-
tients per group to change the results of this pooling.
However, it remains to be examined whether the response
to lithium augmentation represents true augmentation
resulting from synergistic effects or whether the response
is simply owing to the antidepressant effect of lithium it-
self. Experimental studies supporting the former possi-
bility will be reviewed below. From the clinical point of
view, arguments for a true augmentation effect derive
from a controlled clinical trial showing that the antide-
pressant effects of lithium addition were significantly
higher in amitriptyline-pretreated depression patients,
compared with placebo-pretreated patients, who showed
no improvement after a 3-week treatment [17]. In sum-
mary, a randomized, double-blind study is warranted
which investigates the effects of lithium alone and com-
pares them with the effects of lithium in combination
with an antidepressant.

38 Neuropsychobiology 2010;62:36–42 Bauer /Adli /Bschor /Pilhatsch /Pfennig /

Sasse /Schmid /Lewitzka
 Comparator Studies of Lithium Augmentation
Rarely have two augmentation strategies been com-
pared with each other under similar conditions, thus the
relative magnitude of their effects is largely unknown.
Among the comparators were electroconvulsive therapy
[18], monoamine oxidase inhibitors [19, 20], thyroid hor-
mone [21], carbamazepine [22, 23], and high-dose SSRIs
or tricyclic augmentation in SSRI users [24]. In these
studies, there has been no dramatic difference between
lithium augmentation and any other strategy, although
the varied quality of some studies – for example problems
with trial duration, use of subtherapeutic doses of lithium
and low power – should preclude drawing definite con-
clusions.
Continuation Phase and Discontinuation Studies
One randomized controlled trial has examined the ef-
ficacy of lithium augmentation in the continuation treat-
ment phase of unipolar major depressive disorder [25].
Twenty-nine patients with a refractory major depressive
episode, single or recurrent, who had responded to acute
lithium augmentation therapy during an open-label 6-
week study were randomized after a 2- to 4-week stabili-
zation period to a double-blind continuation treatment
for another 4 months with either lithium (n = 14) or pla-
cebo (n = 15). The antidepressant was continued at the
same dosage throughout the study. Seven of the 15 pa-
tients on placebo suffered from a relapse (5 depressive
and 2 with a first manic episode) in the double-blind
study phase, while no patients from the lithium group
relapsed. Even more patients relapsed during the subse-
quent open-label 6-month phase after lithium was with-
drawn in the group previously receiving lithium [26]. It
was concluded that patients who respond to lithium aug-
mentation should be maintained on lithium augmenta-
tion for a minimum of 12 months or even longer [26].
The effects of gradual discontinuation of lithium aug-
mentation therapy were assessed in a randomized, pla-
cebo-controlled discontinuation study in 12 elderly pa-
tients who had responded to lithium augmentation dur-
ing their most recent refractory unipolar depressive
episode [27]. Patients were randomized to receive contin-
ued lithium augmentation or matching placebo; 2 of 6
patients in the lithium maintenance group had a recur-
rence of depression at 61 and 96 weeks, respectively, im-
mediately after a stressful life event. Similarly, 2 of 6 pa-
tients had a recurrence in the placebo group at 7 and 92
Lithium Augmentation
weeks, respectively, without any apparent changes in life
stresses. In a second, naturalistic discontinuation study
in an elderly group of patients with major depressive dis-
order, about half of the patients relapsed following dis-
continuation of lithium augmentation [28]. In a recent
review article [29], it was concluded that there is a sig-
nificant risk of relapse in elderly patients whose lithium
augmentation therapy for unipolar depression is discon-
tinued.
Predictors of Response and Practical Use of Lithium
Augmentation
A series of studies have investigated clinical and bio-
logical factors in lithium augmentation trials to allow
outcome prediction [17, 30–33]. Age and gender have con-
sistently been found not to be associated with response.
Some studies have observed that bipolar patients respond
better than unipolar patients [34], but this has not been
confirmed by others, likely because most patients en-
rolled in the augmentation studies suffered from unipo-
lar depression [35]. An analysis of 71 depressed patients
refractory to treatment with a tricyclic antidepressant
demonstrated that patients with a more severe depressive
syndrome were more likely to respond to lithium aug-
mentation [33].
During the past decade, we have administered lithium
augmentation in a fast titrating regimen in adults without
major adverse events in depressed in- and outpatients. In
adults (age up to 55 years; in elderly patients slower), lith-
ium carbonate is started on a daily dose of 450 mg (equiv-
alent to approximately 12 mmol/day), and the dose is in-
creased to 900 mg on the second day. This scheme leads
to lithium serum levels of 0.5–0.7 mmol/l in most pa-
tients. The first dose adjustment can be performed after
achieving a steady state, typically 5 days after the last
change in dosing. Treatment of about 4 weeks allows as-
sessment of the patient’s response.
Mechanisms of Lithium Augmentation
The underlying mechanisms of action involved in the
potentiatory effect of lithium is still unclear and several
hypotheses have been suggested such as activity and
modulation on serotonin (5-HT) neurotransmission and
endocrine systems [36–38]. Initially, de Montigny and
colleagues [17, 39] postulated that a pharmacodynamic
action mediated via the serotonergic systems may ac-
Neuropsychobiology 2010;62:36–42 39
count for the synergistic effect of lithium when added to
a tricyclic antidepressant. From animal studies there is
robust evidence that lithium augmentation increases 5-
HT neurotransmission, possibly through a synergistic
action of lithium and the antidepressant on brain 5-HT
pathways. Using microdialysis techniques in animals,
addition of lithium to chronic citalopram therapy further
elevated basal levels of 5-HT in the rat ventral hippocam-
pus [40]. Further evidence for a ‘true’ augmentation effect
derived from animal studies showed that, in contrast to
lithium alone, the addition of lithium to antidepressant
treatment with the SSRI, citalopram potentiated presyn-
aptic serotonergic function in rats [41]. Specifically, some
authors suggested that the effect of lithium on 5-HT neu-
rotransmission could be linked to a partial agonist activ-
ity on 5-HT1B autoreceptors or to a modulatory activity
on these receptors [38]. In a recent series of experiments,
the effects of lithium were investigated in a battery of
standard behavioral tests (e.g. Porsolt’s forced swim test,
open-field test) that are considered animal models of de-
pression. In these studies, behavior was robustly affected
dose dependently by chronic lithium treatment [42, 43]
suggesting lithium’s genuine antidepressant properties.
Remarkably, these lithium-sensitive behaviors were also
observed in mice lacking one copy of the gene encoding
GSK3␤, a well-established direct target of lithium [42].
Pharmacogenetic approaches to assess genetic influ-
ences on response probability to lithium augmentation
have also revealed some promising results. In a pilot
study, the 5-HT transporter gene-linked polymorphic re-
gion (5-HTTLPR) allele variant’s effect on lithium aug-
mentation was analyzed in 50 antidepressant-nonrespon-
sive patients [44]. Patients homozygous for the s allele of
the 5-HTTLPR had a more favorable response compared
with those heterozygous (hazard ratio = 6.9; p = 0.005) or
homozygous for the l allele (hazard ratio = 4.5; p = 0.003).
These findings support a differential effect of the 5-HT-
TLPR gene on treatment augmentation and the s/s geno-
type might predict an individual’s risk of antidepressant
nonresponsiveness and sensitivity to augmentative drugs
such as lithium.
Another pharmacogenetic study investigated the as-
sociation of the GSK3␤ –50T/C single nucleotide poly-
morphism (SNP) and response to lithium augmentation
in 81 unipolar depressed patients [45]. Inhibition of
GSK3␤ – an intracellular kinase, highly expressed in the
brain – has been associated with neurotrophic and neu-
roprotective effects. Most interestingly, lithium is a direct
and significant inhibitor of GSK3␤. A –50T/C SNP local-
ized within the promoter region of the GSK3␤ gene has
40 Neuropsychobiology 2010;62:36–42
previously been shown to be associated with response to
lithium prophylaxis in bipolar disorder [46]. Similarly,
carriers of the C allele of the –50T/C SNP showed a sig-
nificantly better response to lithium augmentation (haz-
ard ratio = 2.70, p = 0.007) with a mean remission rate of
56.2% after 4 weeks compared to 31% in patients with the
TT genotype [45]. These results suggest a predictive role
of the –50T/C SNP of the GSK3␤ gene for response to
lithium augmentation treatment in depressed patients
who do not respond sufficiently to monotherapy with an
antidepressant. However, these promising data require
confirmation in larger samples to be applicable in clinical
routine care. Also, the functional relevance of the GSK3␤
–50T/C SNP needs to be further investigated.
Conclusion
Augmentation of antidepressants with lithium is the
best-evidenced augmentation therapy in the treatment of
depressed patients who do not respond to standard anti-
depressants. The evidence reviewed here supports the
recommendation of lithium augmentation as a first-line
therapy for nonresponding and refractory depressed pa-
tients [3, 4, 6]. In depressed patients who respond to lith-
ium augmentation, effective lithium doses should be con-
tinued in combination with the antidepressant for at least
12 months after remission, in those patients with recur-
rent depression even longer [25]. Unfortunately, this ef-
fective and generally well-tolerated strategy is widely un-
derutilized in clinical practice.
References 1 Davis JM: Lithium maintenance of unipolar
depression; in Bauer M, Grof P, Müller-Oer-
linghausen B (eds): Lithium in Neuropsychi-
atry – The Comprehensive Guide. Abing-
don, Informa Healthcare UK Ltd, 2006, pp
99–108.
2 Bauer M, Crossley NA, Gerber S, Bschor T:
The acute antidepressive effects of lithium:
from monotherapy to augmentation therapy
in major depression; in Bauer M, Grof P,
Müller-Oerlinghausen B (eds): Lithium in
Neuropsychiatry – The Comprehensive
Guide. Abingdon, Informa Healthcare UK
Ltd, 2006, pp 109–127.
3 Bauer M, Bschor T, Pfennig A, Whybrow PC,
Angst J, Versiani M, Möller HJ: World Fed-
eration of Societies of Biological Psychiatry
(WFSBP) guidelines for biological treatment
of unipolar depressive disorders in primary
care. World J Biol Psychiatry 2007; 8:67–104.
Bauer /Adli /Bschor /Pilhatsch /Pfennig /
Sasse /Schmid /Lewitzka
 4 Bauer M, Whybrow PC, Angst J, Versiani M,
Möller HJ: World Federation of Societies of
Biological Psychiatry (WFSBP) guidelines
for biological treatment of unipolar depres-
sive disorders. 1. Acute and continuation
treatment of major depressive disorder.
World J Biol Psychiatry 2002; 3:5–43.
5 Thase ME: Augmentation strategies for de-
pression: history and concepts. CNS Spectr
2007;12(suppl 22):3–5.
6 Carvalho AF, Machado JR, Cavalcante JL:
Augmentation strategies for treatment-resis-
tant depression. Curr Opin Psychiatry 2008;
22:7–12.
7 De Montigny C, Grunberg F, Mayer A, De-
schenes JP: Lithium induces rapid relief of
depression in tricyclic antidepressant drug
non-responders. Br J Psychiatry 1981; 138:
252–256.
8 Bauer M, Adli M, Baethge C, Berghöfer A,
Sasse J, Heinz A, Bschor T: Lithium augmen-
tation therapy in refractory depression: clin-
ical evidence and neurobiological mecha-
nisms. Can J Psychiatry 2003;48:440–446.
9 Crossley NA, Bauer M: Acceleration and
augmentation of antidepressants with lithi-
um for depressive disorders: two meta-anal-
yses of randomized, placebo-controlled tri-
als. J Clin Psychiatry 2007;68:935–940.
10 Kantor D, McNevin S, Leichner P, Harper D,
Krenn M: The benefit of lithium carbonate
adjunct in refractory depression – fact or fic-
tion? Can J Psychiatry 1986;31:416–418.
11 Zusky PM, Biederman J, Rosenbaum JF,
Manschreck TC, Gross CC, Weilberg JB,
Gastfriend DR: Adjunct low-dose lithium
carbonate in treatment-resistant depression:
a placebo-controlled study. J Clin Psycho-
pharmacol 1988;8:120–124.
12 Browne M, Lapierre YD, Hrdina PD, Horn E:
Lithium as an adjunct in the treatment of
major depression. Int Clin Psychopharmacol
1990;5:103–110.
13 Stein G, Bernadt M: Lithium augmentation
therapy in tricyclic-resistant depression. A
controlled trial using lithium in low and nor-
mal doses. Br J Psychiatry 1993; 162: 634–
640.
14 Nierenberg AA, Papakostas GI, Petersen T,
Montoya HD, Worthington JJ, Tedlow J,
Alpert JE, Fava M: Lithium augmentation of
nortriptyline for subjects resistant to multi-
ple antidepressants. J Clin Psychopharmacol
2003;23:92–95.
15 Bschor T, Bauer M: Is successful lithium aug-
mentation limited to serotonergic antide-
pressants? J Clin Psychopharmacol 2004;24:
240–241.
16 Bauer M, Döpfmer S: Lithium augmentation
in treatment-resistant depression: meta-
analysis of placebo-controlled studies. J Clin
Psychopharmacol 1999;19:427–434.
Lithium Augmentation
17 de Montigny C, Cournoyer G, Morissette R,
Langlois R, Caille G: Lithium carbonate neu-
robiologic actions of tricyclic antidepressant
drugs and lithium ion on the serotonin sys-
tem. Arch Gen Psychiatry 1983; 40: 1327–
1334.
18 Dinan TG, Barry S: A comparison of electro-
convulsive therapy with a combined lithium
and tricyclic combination among depressed
tricyclic nonresponders. Acta Psychiatr
Scand 1989;80:97–100.
19 Hoencamp E, Haffmans PM, Dijken WA,
Hoogduin CA, Nolen WA, van Dyck R: Bro-
faromine versus lithium addition to mapro-
tiline. A double-blind study in maprotiline
refractory depressed outpatients. J Affect
Disord 1994;30:219–227.
20 Kok RM, Vink D, Heeren TJ, Nolen WA:
Lithium augmentation compared with phen-
elzine in treatment-resistant depression in
the elderly: an open, randomized, controlled
trial. J Clin Psychiatry 2007;68:1177–1185.
21 Joffe RT, Singer W, Levitt AJ, MacDonald C:
A placebo-controlled comparison of lithium
and triiodothyronine augmentation of tricy-
clic antidepressants in unipolar refractory
depression. Arch Gen Psychiatry 1993a;50:
387–393.
22 Rybakowski JK, Suwalska A, Chlopocka-
Wozniak M: Potentiation of antidepressants
with lithium or carbamazepine in treat-
ment-resistant depression. Neuropsychobi-
ology 1999; 40:134–139.
23 Schüle C, Baghai TC, Eser D, Nothdurfter C,
Rupprecht R: Lithium but not carbamaze-
pine augments antidepressant efficacy of
mirtazapine in unipolar depression: an
open-label study. World J Biol Psychiatry
2008;25:1–10.
24 Fava M, Alpert J, Nierenberg A, Lagomasino
I, Sonawalla S, Tedlow J, Worthington J, Baer
L, Rosenbaum JF: Double-blind study of
high-dose fluoxetine versus lithium or de-
sipramine augmentation of fluoxetine in
partial responders and nonresponders to
fluoxetine. J Clin Psychopharmacol 2002;22:
379–387.
25 Bauer M, Bschor T, Kunz D, Berghöfer A,
Ströhle A, Müller-Oerlinghausen B: Double-
blind, placebo-controlled trial of the use of
lithium to augment antidepressant medica-
tion in continuation treatment of unipolar
major depression. Am J Psychiatry 2000;157:
1429–1435.
26 Bschor T, Berghöfer A, Ströhle A, Kunz D,
Adli M, Müller-Oerlinghausen B, Bauer M:
How long should the lithium augmentation
strategy be maintained? A 1-year follow-up
of a placebo-controlled study in unipolar re-
fractory major depression. J Clin Psycho-
pharmacol 2002;22:427–430.
27 Hardy BG, Shulman KI, Zucchero C: Gradu-
al discontinuation of lithium augmentation
in elderly patients with unipolar depression.
J Clin Psychopharmacol 1997;17:22–26.
Neuropsychobiology 2010;62:36–42
28 Fahy S, Lawlor BA: Discontinuation of lithi-
um augmentation in an elderly cohort. Int J
Geriatr Psychiatry 2001;16:1004–1009.
29 Ross J: Discontinuation of lithium augmen-
tation in geriatric patients with unipolar de-
pression: a systematic review. Can J Psychia-
try 2008;53:117–120.
30 Schöpf J, Baumann P, Lemarchand T, Rey M:
Treatment of endogenous depressions resis-
tant to tricyclic antidepressants or related
drugs by lithium addition. Results of a pla-
cebo-controlled double-blind study. Phar-
macopsychiatry 1989;22:183–187.
31 Joffe RT, Levitt AJ, Bagby RM, MacDonald
C, Singer W: Predictors of response to lithi-
um and triiodothyronine augmentation of
antidepressants in tricyclic non-responders.
Br J Psychiatry 1993b;163: 574–578.
32 Alvarez E, Perez-Sola V, Perez-Blanco J,
Queralto JM, Torrubia R, Noguera R: Pre-
dicting outcome of lithium added to antide-
pressants in resistant depression. J Affect
Disord 1997;42:179–186.
33 Bschor T, Canata B, Müller-Oerlinghausen
B, Bauer M: Predictors of response to lithium
augmentation in tricyclic antidepressant-re-
sistant depression. J Affect Disord 2001; 64:
261–265.
34 Rybakowski J, Matkowski K: Adding lithium
to antidepressant therapy: factors related to
therapeutic potentiation. Eur Neuropsycho-
pharmacol 1992;2:161–165.
35 Price LH, Charney DS, Heninger GR: Vari-
ability of response to lithium augmentation
in refractory depression. Am J Psychiatry
1986;143:1387–1392.
36 Chenu F, Bourin M: Potentiation of antide-
pressant-like activity with lithium: mecha-
nism involved. Curr Drug Targets 2006; 7:
159–163.
37 Bschor T, Adli M, Baethge C, Eichmann U,
Ising M, Uhr M, Modell S, Künzel H, Müller-
Oerlinghausen B, Bauer M: Lithium aug-
mentation increases the ACTH and cortisol
response in the combined DEX/CRH test in
unipolar major depression. Neuropsycho-
pharmacology 2002; 27:470–478.
38 Bschor T, Baethge C, Adli M, Eichmann U,
Ising M, Uhr M, Modell S, Künzel H, Müller-
Oerlinghausen B, Bauer M: Association be-
tween response to lithium augmentation and
the combined DEX/CRH test in major de-
pressive disorder. J Psychiatr Res 2003; 37:
135–143.
39 de Montigny C, Aghajanian GK: Tricyclic
antidepressants: long-term treatment in-
creases responsivity of rat forebrain neurons
to serotonin. Science 1978; 202:1303–1306.
40 Wegener G, Bandpey Z, Heiberg IL, Mork A,
Rosenberg R: Increased extracellular sero-
tonin level in rat hippocampus induced by
chronic citalopram is augmented by sub-
chronic lithium: neurochemical and behav-
ioural studies in the rat. Psychopharmacol-
ogy (Berl) 2003;166:188–194.
41
41 Okamoto Y, Motohasi N, Hayakawa H, Mu-
raoka M, Yamawaki S: Addition of lithium to
chronic antidepressant treatment potenti-
ates presynaptic serotonergic function with-
out changes in serotonergic receptors in the
rat cerebral cortex. Neuropsychobiology
1996;33:17–20.
42 O’Brien WT, Harper AD, Jové F, Woodgett
JR, Maretto S, Piccolo S, Klein PS: Glycogen
synthase kinase-3␤ haploinsufficiency mim-
ics the behavioral and molecular effects of
lithium. J Neurosci 2004;24:6791–6798.
43 Bersudsky Y, Shaldubina A, Belmaker RH:
Lithium’s effect in forced-swim test is blood
level dependent but not dependent on weight
loss. Behav Pharmacol 2007;18:77–80.
44 Stamm TJ, Adli M, Kirchheiner J, Smolka
MN, Kaiser R, Tremblay PB, Bauer M: Sero-
tonin transporter gene and response to lith-
ium augmentation in depression. Psychiatr
Genet 2008;18:92–97.
45 Adli M, Hollinde DL, Stamm T, Wiethoff K,
Tsahuridu M, Kirchheiner J, Heinz A, Bauer
M: Response to lithium augmentation in de-
pression is associated with the glycogen syn-
thase kinase 3-beta –50T/C single nucleotide
polymorphism. Biol Psychiatry 2007; 62:
1295–1302.
46 Benedetti F, Serretti A, Pontiggia A, Ber-
nasconi A, Lorenzi C, Colombo C, Smeraldi
E: Long-term response to lithium salts in bi-
polar illness is influenced by the glycogen
synthase kinase 3-beta –50 T/C SNP. Neuro-
sci Lett 2005;376:51–55.
47 Heninger GR, Charney DS, Sternberg DE:
Lithium carbonate augmentation of antide-
pressant treatment. An effective prescrip-
tion for treatment-refractory depression.
Arch Gen Psychiatry 1983;40:1335–1342.
48 Katona CL, Abou-Saleh MT, Harrison DA,
Nairac BA, Edwards DR, Lock T, Burns RA,
Robertson MM: Placebo-controlled trial of
lithium augmentation of fluoxetine and lofe-
pramine.Br J Psychiatry 1995;166:80–86.
49 Baumann P, Nil R, Souche A, Montaldi S,
Baettig D, Lambert S, Uehlinger C, Kasas A,
Amey M, Jonzier-Perey M: A double-blind,
placebo-controlled study of citalopram with
and without lithium in the treatment of ther-
apy-resistant depressive patients: a clinical,
pharmacokinetic, and pharmacogenetic in-
vestigation. J Clin Psychopharmacol 1996;
16:307–314.

42 Neuropsychobiology 2010;62:36–42 Bauer /Adli /Bschor /Pilhatsch /Pfennig /

Sasse /Schmid /Lewitzka
Copyright: S. Karger AG, Basel 2010. Reproduced with the permission of S. Karger AG, Basel. Further
reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright
holder.